期刊
HUMAN MOLECULAR GENETICS
卷 25, 期 24, 页码 5483-5489出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw348
关键词
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资金
- Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA)
- National Institutes of Health, Department of Health and Human Services
- Department of Defence [W81XWH-09-2-0128]
- Michael J Fox Foundation for Parkinson's Research
- National Institutes of Health [R01NS037167, R01CA141668, P50NS071674]
- American Parkinson Disease Association (APDA)
- Barnes Jewish Hospital Foundation
- Greater St Louis Chapter of the APDA
- Princes Beatrix Fonds
- Forschungszentrum far Umwelt und Gesundheit
- German Federal Ministry of Education, Science, Research, and Technology
- State of Bavaria
- German National Genome Network [NGFN 01GS08134]
- German Federal Ministry of Education and Research [NGFN 01GR0468]
- ERA-NET NEURON [01EW0908]
- Helmholtz Alliance Mental Health in an Ageing Society [HA-215]
- Initiative and Networking Fund of the Helmholtz Association
- French National Agency of Research [ANR-08-MNP-012]
- France-Parkinson Association
- French program Investissements d'avenir funding [ANR-10-LAIHU-06]
- Assistance Publique-HOpitaux de Paris (PHRC) [AOR-08010]
- Landspitali University Hospital Research Fund
- Icelandic Research Council
- European Community
- IAPP on novel genetic and phenotypic markers of Parkinson's disease and Essential Tremor (MarkMD) [PIAP-GA-2008-230596]
- Medical Research Council
- Wellcome Trust [WT089698/Z/09/Z, 076113, 085475, 090355]
- Parkinson's UK [8047, J-0804, F1002, F-1201]
- Medical Research Council [G0700943, G1100643, MR/L010933/1, MR/N026004/1]
- GE Healthcare
- Elan/Prothena
- Biotechnology and Biological Sciences Research Council Collaborative Award in Science and Engineering (BBSRC CASE) [BB/M01722211]
- Research Councils UK
- [Z01-AG000949-02]
- [Z01-ES101986]
- Medical Research Council [MR/L010305/1, G1100643, MR/N026004/1, MR/L010933/1, MC_PC_09003, MC_G0901330, MR/L501554/1, G0700943] Funding Source: researchfish
- Parkinson's UK [G-1107, J-0804, F-1201, K-1501, F-1002] Funding Source: researchfish
- BBSRC [1644051] Funding Source: UKRI
- MRC [MR/N026004/1, MC_PC_09003, G1100643, MR/L010933/1, MC_G0901330, G0700943] Funding Source: UKRI
Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (>= 30%) of cases with a recognised primary genetic cause had >= 1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.
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